Retinal diseases, including age-related macular degeneration (AMD), diabetic retinopathy (DR), diabetic macular edema (DME), and retina vein occlusion (RVO), are the leading causes of vision loss and blindness in people over 55 years old. According to the NEI, in 2010 nearly 10 million people in the U.S. suffered from some form of these diseases, whose prevalence is expected to increase to 15 million over 20 years. Recently approved therapies have focused on the exudative (wet) form of AMD, which is characterized by abnormal new vessel formation (neovascularization), and affects an estimated 1.6 million people. Typically, these treatments focus on inhibiting vascular endothelial growth factor (VEGF), a protein that promotes the extravasation from existing vessels as well as the formation of new blood vessels that lack a non-leaky blood- retinal barrier. The most commonly used therapeutics include the biologic drugs LucentisTM, AvastinTM and EyleaTM, which must be administered via injections directly into the vitreous cavity every one or two months. Although these drugs are designed to bind to VEGF and limit its actions, they do not eliminate the source that produces VEGF, and although rare can also be associated with serious side effects including stroke. Moreover, the majority of patients do not have a marked improvement in their vision (e.g., about one-third of the AMD patients get improvement of 3 lines or more on the ETDRS vision chart). Therefore, despite these advances, there is still a major unmet need to develop new treatments that can better address the pathogenesis of these diseases. This project is based on a new therapeutic concept resulting from unique insights on the critical impact of persistent local inflammation that is responsible for the production of VEGF, leading to the initiation and progression of AMD. These efforts led to the identification of a family of localy formed small molecules that reduce local inflammation in AMD and also suppress the production of VEGF. As a result, it became possible to use these findings to design and validate new biomimetic small molecules as potential therapeutics for neovascular retinal diseases. This proposal is for the development of a new small molecule drug candidate that dramatically reduces abnormal VEGF-mediated effects without directly binding to VEGF. The efficacy of this promising molecule has been validated in animal models, which showed that it is able to reduce the underlying persistent inflammatory response, suppress the VEGF pathway, block neovascularization, and promote regression of the disease. The proposed work will further advance this lead molecule towards the next steps of pre-clinical development, setting the stage for translation into human clinical trials.